AUCTORES
Globalize your Research
Case Report | DOI: https://doi.org/10.31579/2690-8794/088
1 MBBS, MS (OBGYN), DM (Medical Genetics), Foetal Medicine & Medical Geneticist, Artemis Hospitals, Gurgaon, India.
2 MBBS, MD (PGI), MRCOG, FRCOG, Diploma in Pelvic Endoscopy, Department of Minimal Access Surgery (Gynaecology), Fortis Memorial Research Institute, Gurgaon.
3 MBBS, MD (Obst & Gynae), Department of Minimal Access Surgery (Gynaecology), Fortis Memorial Research Institute, Gurgaon.
4 MBBS, MS (Obst & Gynae), Department of Obstetrics & Gynecology, Artemis Health Institute, India.
5 MBBS, DNB (Obst & Gynae), MNAMS, Department of Obstetrics & Gynecology, Artemis Health Institute, India.
6 MBBS, MD (Radiodiagnosis), Department of Radiology, Manipal Hospitals, Dwarka, India
*Corresponding Author: Gupta Ashutosh, MBBS, MS (OBGYN), DM (Medical Genetics), Foetal Medicine & Medical Geneticist, Artemis Hospitals, Gurgaon, India.
Citation: Gupta Ashutosh, Aneja Anjila, Bahl Neena, Arora Rupam, Sehgal Renu Raina, Saini Pankaj (2021) Foetal phenotype of Maat-Kievit-Brunner type Ohdo syndrome. Clinical Medical Reviews and Reports. 3(8); DOI: 10.31579/2690-8794/088
Copyright: © 2021, Gupta Ashutosh, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received: 02 June 2021 | Accepted: 10 September 2021 | Published: 25 September 2021
Keywords: med12; allelic; mkb, ohdo syndrome; micrognathia; cryptorchidism; blepharophimosis; philtrum; vermilion, foetal; maat-kievit-brunner (mkb) type ohdo syndrome; blepharophimosis-mental retardation syndrome; x linked ohdo syndrome
MED12 is a member of large Mediator complex; has a very crucial and central role in RNA polymerase II transcription; regulating cell signals involved in growth, development and differentiation.
Different MED12 mutations may have different clinical presentation representing an allelic disorder.
Maat-Kievit-Brunner (MKB) type Ohdo syndrome; has a typical facial features comprising of blepharophimosis, ptosis, long flat philtrum with thin vermilion, micrognathia with microstomia, scrotal hypoplasia with cryptorchidism, joint hypermobility with clinodactyly with overriding toes,
A primigravida on antenatal ultrasound was detected to have growth restriction, corpus callosal dysgenesis, syndactyly and suspected ambiguous genitalia. Invasive testing and exome sequencing revealed hg19chrX:MED12:c.2315A>G: (p.Lys772Arg);MED12(NM_005120.3):c.2315A>G: (p.Lys772Arg) leading to provisional diagnosis of X linked Ohdo syndrome with an overlap with FG. Missense mutation was classified to be PM2; PP3 (ACMG)
Clinical presentation, phenotype and mutational analysis led to provisional diagnosis of X linked Ohdo syndrome. Maat-Kievit-Brunner type of Ohdo syndrome is a rare condition and this is probably the first case describing foetal phenotype of MKB type of Ohdo syndrome.
In 1974, Opitz and Kaveggia described a X-linked recessive intellectual disability syndrome characterized by relative macrocephaly, hypertelorism, downslant palpebral fissures, prominent forehead with frontal hair upsweep with broad thumbs and halluces [1].
In 1984, Lujan et al reported four male patients with marfanoid habitus, long narrow face, small mandible with high-arched palate, hypernasal voice with intellectual disability [2].
In 1993, Maat-Kievit et al delineated a X-linked Ohdo syndrome; characterized by failure to thrive with facial features comprising blepharophimosis, ptosis, wide depressed nasal bridge, long philtrum, thin vermilion, micrognathia with microstomia, scrotum hypoplasia with cryptorchidism, joint hypermobility, overriding toes with clinodactyly, cafe-au-lait spots, developmental delay with hearing disability [3].
In 2007, Risheg et al documented a recurrent MED12 mutation (p.Arg961Trp) which was earlier diagnosed as FG (Opitz–Kaveggia) syndrome [5]. Reported a different mutation (p.Gly958Glu) with similar clinical phenotype [4]. Demonstrated (p.Asn1007Ser) MED12 mutation in a family originally diagnosed as Lujan–Fryns syndrome [6].
Vulto-van Silfhout [11] reported (p.Arg1148His, p.Ser1165Pro and p.His1729Asn) mutations in a family originally documented as MKB. [7] Isidor et al. identified (p.Arg1148His) mutation in two male siblings with phenotype similar to those of MKB [8].
It is now established that MED12 mutations have different clinical presentation representing an allelic disorder. (Table 1) [9].
Maat-Kievit-Brunner (MKB) type Ohdo syndrome has a X-linked recessive inheritance pattern with typical facial features like thick alae nasi, blepharophimosis, ptosis, wide depressed nasal bridge, large bulbous nose, long flat philtrum with thin vermilion, micrognathia with microstomia, feeding difficulties, scrotal hypoplasia with cryptorchidism, joint hypermobility with clinodactyly with overriding toes, cafe-au-lait spots, hearing disability. Facial features become more pronounced with age with characteristic triangular facies [1]. It may have mild to severe developmental delay with delayed motor milestones with behavioural problems with mental retardation.
Maat-Kievit-Brunner type of Ohdo syndrome is a rare condition and this is probably the first case describing foetal phenotype of MKB type of Ohdo syndrome. It is caused MED12 gene (mediator complex subunit 12) mutations; which is a subunit of the mediator complex, a group of about 25 proteins which regulates gene activity. It physically links transcription factors to turn on or off the genes. MED12 protein is involved in development of the neurons, in several chemical signalling pathways to regulate cell growth, migration and differentiation.
A booked primigravida at 19 weeks of pregnancy with no high risk factor was evaluated in the department of Foetal Medicine at Artemis Hospital for foetal anomaly scan. It is a non-consanguineous marriage and no other male member of the extended family has been affected with intellectual disability or dysmorphism.
On antenatal ultrasound, high riding / upward displacement of 3rd ventricle was noticed with divergent frontal horns suggestive of corpus callosal dysgenesis (Figure 1-a). Further evaluation showed syndactly of 2 and 3rd toe of the right foot; however 2 and 3rd toes of the left foot were seen separate (Figure 1-b). Foetus was also identified to have hypospadias with suspected sex reversal or ambiguous genitalia (Fig 1-c). There was also an element of growth restriction by 1 week at 19 weeks of gestation (Figure 1-d).
Axial scan of foetal brain showing high riding 3rd ventricle; upward displacement of the third ventricle; increased separation of the hemispheres, Coronal scan of a normal foetal brain demonstrating absence of the corpus callosum (genu), an increased distance between the frontal horns and their abnormal aspect suggestive of corpus callosal dysgenesis (a)
In the advent of foetal growth restriction, corpus callosal dysgenesis, syndactyly and suspected ambiguous genitalia; the consult and (parents) was counselled for invasive foetal testing; amniocentesis was done and on exclusion of maternal cell contamination; foetal DNA was processed for exome sequencing. Ambiguous genitalia in the clinical picture prompted and pointed towards foetal cholesterol pathway defect thus an exome sequencing was ordered. With all this information, possibilities couple decided for an irreversible decision regarding the pregnancy.
Postnatal examination of the foetus showed penoscrotal hypospadias, syndactyly in 2&3rd toe in the right feet and normally separated 2 and 3rd toe in the left toe (Figure 2-a) corroborating the main antenatal findings. It also revealed bilateral low set ears, micrognathia (Figure 2-b), thin vermilion, long philtrum and blepharophimosis (bilateral and both eye lids could not be separated completely with considerable effort) (Figure 2-c) corroborating the diagnosis of X linked Ohdo syndrome. The consult and (parents) gently refused for further postnatal (post mortem) examination of the foetus.
Exome sequencing revealed hemizygous missense variation single-nucleotide variant (SNV) in exon 16 of the MED12 gene (Xq13.1); with amino acid substitution of Arginine for Lysine at codon 772, c.2315A>G (p.Lys772Arg); hg19chrX:MED12:c.2315A>G:(p.Lys772Arg); MED12(NM_005120.3):c.2315A>G:(p.Lys772Arg) leading to provisional diagnosis of possible MED12 related disorder; X linked Ohdo syndrome or FG syndrome.
The same mutation was confirmed by sanger sequencing and identified in the asymptomatic mother. In silico prediction of the variant has been identified to be damaging by LRT and Mutaion Taster.
In accordance to the American College of Medical Genetics and Genomics (ACMG) criteria for classifying pathogenic variants; the variation was classified as variant of uncertain significance and the missense mutation was classified to be PM2 (absent from controls or at extremely low frequency if recessive) and PP3 (multiple lines of computational evidence support a deleterious effect on the gene or gene product). (19)
Table no 1 elaborates characteristic features of the Ohdo syndrome; some of which detected antenatally were confirmed and remaining were identified by postnatal examination. Maat-Kievit et al. (1993), Verloes et al. (2006) and Vulto-van Silfhout et al. (2013) (3, 7, 14) have reported missense mutations in MED 12 to be causative for Maat-Kievit-Brunner type Ohdo syndrome (Table 2). Table no 3 describes the genotype – phenotype corelation of MED 12 mutations.
Clinical presentation, phenotype and mutational analysis led to provisional diagnosis of possible MED12 related disorder; X linked Ohdo syndrome or FG syndrome.
MED12 being a member of large Mediator complex; has a very crucial and central role in RNA polymerase II transcription. It regulates the cell signals involved in growth, development and differentiation.
MKB is a rare condition; X-linked recessive inheritance; very typical pattern of facial features which are difficult to be detected on antenatally. It is probably the first case of detection of foetal phenotype of MKB.
With ever increasing use of massive parallel sequencing with next-generation sequencers, it is likely that more MED12 distinctive phenotype and mutations will be detected. This also helps in identifying the genetic aetiology in families with intellectual disability and dysmorphic features and to broaden genotype–phenotype correlations.
Clearly Auctoresonline and particularly Psychology and Mental Health Care Journal is dedicated to improving health care services for individuals and populations. The editorial boards' ability to efficiently recognize and share the global importance of health literacy with a variety of stakeholders. Auctoresonline publishing platform can be used to facilitate of optimal client-based services and should be added to health care professionals' repertoire of evidence-based health care resources.
Journal of Clinical Cardiology and Cardiovascular Intervention The submission and review process was adequate. However I think that the publication total value should have been enlightened in early fases. Thank you for all.
Journal of Women Health Care and Issues By the present mail, I want to say thank to you and tour colleagues for facilitating my published article. Specially thank you for the peer review process, support from the editorial office. I appreciate positively the quality of your journal.
Journal of Clinical Research and Reports I would be very delighted to submit my testimonial regarding the reviewer board and the editorial office. The reviewer board were accurate and helpful regarding any modifications for my manuscript. And the editorial office were very helpful and supportive in contacting and monitoring with any update and offering help. It was my pleasure to contribute with your promising Journal and I am looking forward for more collaboration.
We would like to thank the Journal of Thoracic Disease and Cardiothoracic Surgery because of the services they provided us for our articles. The peer-review process was done in a very excellent time manner, and the opinions of the reviewers helped us to improve our manuscript further. The editorial office had an outstanding correspondence with us and guided us in many ways. During a hard time of the pandemic that is affecting every one of us tremendously, the editorial office helped us make everything easier for publishing scientific work. Hope for a more scientific relationship with your Journal.
The peer-review process which consisted high quality queries on the paper. I did answer six reviewers’ questions and comments before the paper was accepted. The support from the editorial office is excellent.
Journal of Neuroscience and Neurological Surgery. I had the experience of publishing a research article recently. The whole process was simple from submission to publication. The reviewers made specific and valuable recommendations and corrections that improved the quality of my publication. I strongly recommend this Journal.
Dr. Katarzyna Byczkowska My testimonial covering: "The peer review process is quick and effective. The support from the editorial office is very professional and friendly. Quality of the Clinical Cardiology and Cardiovascular Interventions is scientific and publishes ground-breaking research on cardiology that is useful for other professionals in the field.
Thank you most sincerely, with regard to the support you have given in relation to the reviewing process and the processing of my article entitled "Large Cell Neuroendocrine Carcinoma of The Prostate Gland: A Review and Update" for publication in your esteemed Journal, Journal of Cancer Research and Cellular Therapeutics". The editorial team has been very supportive.
Testimony of Journal of Clinical Otorhinolaryngology: work with your Reviews has been a educational and constructive experience. The editorial office were very helpful and supportive. It was a pleasure to contribute to your Journal.
Dr. Bernard Terkimbi Utoo, I am happy to publish my scientific work in Journal of Women Health Care and Issues (JWHCI). The manuscript submission was seamless and peer review process was top notch. I was amazed that 4 reviewers worked on the manuscript which made it a highly technical, standard and excellent quality paper. I appreciate the format and consideration for the APC as well as the speed of publication. It is my pleasure to continue with this scientific relationship with the esteem JWHCI.
This is an acknowledgment for peer reviewers, editorial board of Journal of Clinical Research and Reports. They show a lot of consideration for us as publishers for our research article “Evaluation of the different factors associated with side effects of COVID-19 vaccination on medical students, Mutah university, Al-Karak, Jordan”, in a very professional and easy way. This journal is one of outstanding medical journal.
Dear Hao Jiang, to Journal of Nutrition and Food Processing We greatly appreciate the efficient, professional and rapid processing of our paper by your team. If there is anything else we should do, please do not hesitate to let us know. On behalf of my co-authors, we would like to express our great appreciation to editor and reviewers.
As an author who has recently published in the journal "Brain and Neurological Disorders". I am delighted to provide a testimonial on the peer review process, editorial office support, and the overall quality of the journal. The peer review process at Brain and Neurological Disorders is rigorous and meticulous, ensuring that only high-quality, evidence-based research is published. The reviewers are experts in their fields, and their comments and suggestions were constructive and helped improve the quality of my manuscript. The review process was timely and efficient, with clear communication from the editorial office at each stage. The support from the editorial office was exceptional throughout the entire process. The editorial staff was responsive, professional, and always willing to help. They provided valuable guidance on formatting, structure, and ethical considerations, making the submission process seamless. Moreover, they kept me informed about the status of my manuscript and provided timely updates, which made the process less stressful. The journal Brain and Neurological Disorders is of the highest quality, with a strong focus on publishing cutting-edge research in the field of neurology. The articles published in this journal are well-researched, rigorously peer-reviewed, and written by experts in the field. The journal maintains high standards, ensuring that readers are provided with the most up-to-date and reliable information on brain and neurological disorders. In conclusion, I had a wonderful experience publishing in Brain and Neurological Disorders. The peer review process was thorough, the editorial office provided exceptional support, and the journal's quality is second to none. I would highly recommend this journal to any researcher working in the field of neurology and brain disorders.
Dear Agrippa Hilda, Journal of Neuroscience and Neurological Surgery, Editorial Coordinator, I trust this message finds you well. I want to extend my appreciation for considering my article for publication in your esteemed journal. I am pleased to provide a testimonial regarding the peer review process and the support received from your editorial office. The peer review process for my paper was carried out in a highly professional and thorough manner. The feedback and comments provided by the authors were constructive and very useful in improving the quality of the manuscript. This rigorous assessment process undoubtedly contributes to the high standards maintained by your journal.
International Journal of Clinical Case Reports and Reviews. I strongly recommend to consider submitting your work to this high-quality journal. The support and availability of the Editorial staff is outstanding and the review process was both efficient and rigorous.
Thank you very much for publishing my Research Article titled “Comparing Treatment Outcome Of Allergic Rhinitis Patients After Using Fluticasone Nasal Spray And Nasal Douching" in the Journal of Clinical Otorhinolaryngology. As Medical Professionals we are immensely benefited from study of various informative Articles and Papers published in this high quality Journal. I look forward to enriching my knowledge by regular study of the Journal and contribute my future work in the field of ENT through the Journal for use by the medical fraternity. The support from the Editorial office was excellent and very prompt. I also welcome the comments received from the readers of my Research Article.
Dear Erica Kelsey, Editorial Coordinator of Cancer Research and Cellular Therapeutics Our team is very satisfied with the processing of our paper by your journal. That was fast, efficient, rigorous, but without unnecessary complications. We appreciated the very short time between the submission of the paper and its publication on line on your site.
I am very glad to say that the peer review process is very successful and fast and support from the Editorial Office. Therefore, I would like to continue our scientific relationship for a long time. And I especially thank you for your kindly attention towards my article. Have a good day!
"We recently published an article entitled “Influence of beta-Cyclodextrins upon the Degradation of Carbofuran Derivatives under Alkaline Conditions" in the Journal of “Pesticides and Biofertilizers” to show that the cyclodextrins protect the carbamates increasing their half-life time in the presence of basic conditions This will be very helpful to understand carbofuran behaviour in the analytical, agro-environmental and food areas. We greatly appreciated the interaction with the editor and the editorial team; we were particularly well accompanied during the course of the revision process, since all various steps towards publication were short and without delay".
I would like to express my gratitude towards you process of article review and submission. I found this to be very fair and expedient. Your follow up has been excellent. I have many publications in national and international journal and your process has been one of the best so far. Keep up the great work.
We are grateful for this opportunity to provide a glowing recommendation to the Journal of Psychiatry and Psychotherapy. We found that the editorial team were very supportive, helpful, kept us abreast of timelines and over all very professional in nature. The peer review process was rigorous, efficient and constructive that really enhanced our article submission. The experience with this journal remains one of our best ever and we look forward to providing future submissions in the near future.
I am very pleased to serve as EBM of the journal, I hope many years of my experience in stem cells can help the journal from one way or another. As we know, stem cells hold great potential for regenerative medicine, which are mostly used to promote the repair response of diseased, dysfunctional or injured tissue using stem cells or their derivatives. I think Stem Cell Research and Therapeutics International is a great platform to publish and share the understanding towards the biology and translational or clinical application of stem cells.
I would like to give my testimony in the support I have got by the peer review process and to support the editorial office where they were of asset to support young author like me to be encouraged to publish their work in your respected journal and globalize and share knowledge across the globe. I really give my great gratitude to your journal and the peer review including the editorial office.
I am delighted to publish our manuscript entitled "A Perspective on Cocaine Induced Stroke - Its Mechanisms and Management" in the Journal of Neuroscience and Neurological Surgery. The peer review process, support from the editorial office, and quality of the journal are excellent. The manuscripts published are of high quality and of excellent scientific value. I recommend this journal very much to colleagues.
Dr.Tania Muñoz, My experience as researcher and author of a review article in The Journal Clinical Cardiology and Interventions has been very enriching and stimulating. The editorial team is excellent, performs its work with absolute responsibility and delivery. They are proactive, dynamic and receptive to all proposals. Supporting at all times the vast universe of authors who choose them as an option for publication. The team of review specialists, members of the editorial board, are brilliant professionals, with remarkable performance in medical research and scientific methodology. Together they form a frontline team that consolidates the JCCI as a magnificent option for the publication and review of high-level medical articles and broad collective interest. I am honored to be able to share my review article and open to receive all your comments.
“The peer review process of JPMHC is quick and effective. Authors are benefited by good and professional reviewers with huge experience in the field of psychology and mental health. The support from the editorial office is very professional. People to contact to are friendly and happy to help and assist any query authors might have. Quality of the Journal is scientific and publishes ground-breaking research on mental health that is useful for other professionals in the field”.
Dear editorial department: On behalf of our team, I hereby certify the reliability and superiority of the International Journal of Clinical Case Reports and Reviews in the peer review process, editorial support, and journal quality. Firstly, the peer review process of the International Journal of Clinical Case Reports and Reviews is rigorous, fair, transparent, fast, and of high quality. The editorial department invites experts from relevant fields as anonymous reviewers to review all submitted manuscripts. These experts have rich academic backgrounds and experience, and can accurately evaluate the academic quality, originality, and suitability of manuscripts. The editorial department is committed to ensuring the rigor of the peer review process, while also making every effort to ensure a fast review cycle to meet the needs of authors and the academic community. Secondly, the editorial team of the International Journal of Clinical Case Reports and Reviews is composed of a group of senior scholars and professionals with rich experience and professional knowledge in related fields. The editorial department is committed to assisting authors in improving their manuscripts, ensuring their academic accuracy, clarity, and completeness. Editors actively collaborate with authors, providing useful suggestions and feedback to promote the improvement and development of the manuscript. We believe that the support of the editorial department is one of the key factors in ensuring the quality of the journal. Finally, the International Journal of Clinical Case Reports and Reviews is renowned for its high- quality articles and strict academic standards. The editorial department is committed to publishing innovative and academically valuable research results to promote the development and progress of related fields. The International Journal of Clinical Case Reports and Reviews is reasonably priced and ensures excellent service and quality ratio, allowing authors to obtain high-level academic publishing opportunities in an affordable manner. I hereby solemnly declare that the International Journal of Clinical Case Reports and Reviews has a high level of credibility and superiority in terms of peer review process, editorial support, reasonable fees, and journal quality. Sincerely, Rui Tao.
Clinical Cardiology and Cardiovascular Interventions I testity the covering of the peer review process, support from the editorial office, and quality of the journal.
